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Autoantibodies, elevated cytokines, and neurocognitive abnormalities in offspring of women with systemic lupus erythematosus: comparison with healthy controls

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Abstract

Introduction

Research describes higher incidence of neurodevelopmental disorders and learning disabilities in offspring of women affected by lupus. Factors implied are pregnancy and delivery adversities and exposure to maternal antibodies and cytokines. Little is known about the offspring immunological condition or the relation between offspring and maternal condition.

Objectives

This study was conducted in order to analyze immunological configuration, psychopathology, and neuropsychological performance of young offspring of women with lupus, in comparison with healthy controls and in relation to maternal psychophysical condition.

Methods

Twenty-one offspring aged 8–17 of 17 women with lupus and 34 controls were recruited. Pregnancy conditions, stress factors, and immunological, psychopathological, and neuropsychological characteristics were compared. Immunological tests included standard lupus screening, lupus-related autoantibodies, antibodies against GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR) (anti-DWEYS Ab), and levels of ten cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GMCSF, IFN-γ, TNF-α).

Results

Offspring had lower leukocyte count (p = 0.001) and higher levels of anti-dsDNA Ab (p = 0.022), anti-DWEYS-GluN2 Ab (p < 0.001), and eight cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α—all p < 0.001—and IFN-γ, p = 0.026) than controls. Their cytokine levels did not differ from their mothers’; 23.9% of offspring met the criteria for a clinical psychiatric diagnosis. No differences were found in intelligence measures. Various neuropsychological scores correlated inversely with maternal psychophysical health.

Conclusions

Offspring’s profile suggests proinflammatory and autoimmune activation. Their rate of psychiatric diagnosis appears higher than in the general population, and their cognitive performance is related to maternal psychophysical health. Longitudinal research might investigate whether immunological and psychosocial conditions influence psychopathology and cognition.

The hypothesized sequence for physical and neuropsychological development for the SLE offspring.

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Abbreviations

Ab :

autoantibodies

ADHD :

attention deficit and hyperactivity disorder

ANA Ab :

anti-nuclear antibodies

Anti-DWEYS-GluN2 Ab :

antibodies against the GluN2 subunit of the NMDAR

anti-RP Ab:

anti-ribosomal P protein antibodies

aPL Ab:

antiphospholipid antibodies

ASD :

autism spectrum disorders

ASLO Ab:

anti-streptolysin-O (ASLO) antibodies

BBB :

blood brain barrier

BDI :

Beck Depression Inventory

BMI :

body mass index

CBA :

cell based assays

CDRS-R :

Children’s Depression Rating Scale—revised

HADS :

Hospital Anxiety and Depression

HC :

healthy controls

IHC :

immunochemistry

LD :

learning disabilities

NMDAR :

N-methyl-D-aspartate receptor

NPSLE :

neuropsychiatric lupus

OCD :

obsessive-compulsive disorder

OCS scale :

obstetrical complication scale

SCARED :

Screen for Child Anxiety Related Emotional Disorders

SES scale:

socioeconomic status scale

SLE :

systemic lupus erythematosus

SLEDAI scale :

SLE Disease Activity Index scale

SLE-O :

offspring of women with SLE

SLES-C :

Stressful Life Events Schedule, child version

SLES-P :

Stressful Life Events Schedule—parent version

SLICC-DI :

Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index scale

WAIS-III :

Wechsler adult intelligence scale 3rd edition

WISC- IV :

the Wechsler intelligence scale for children 4th edition

References

  1. Vinet É, Pineau CA, Clarke AE, Fombonne É, Platt RW, Bernatsky S (2014) Neurodevelopmental disorders in children born to mothers with systemic lupus erythematosus. Lupus 23:1099–1104. https://doi.org/10.1177/0961203314541691

    Article  CAS  PubMed  Google Scholar 

  2. Lee JY, Huerta PT, Zhang J, Kowal C, Bertini E, Volpe BT, Diamond B (2009) Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat Med 15:91–96. https://doi.org/10.1038/nm.1892

    Article  CAS  PubMed  Google Scholar 

  3. DeGiorgio LA, Konstantinov KN, Lee SC et al (2001) A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 7:1189–1193. https://doi.org/10.1038/nm1101-1189

    Article  CAS  PubMed  Google Scholar 

  4. Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702. https://doi.org/10.1523/JNEUROSCI.2178-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42:599–608. https://doi.org/10.1002/1529-0131(199904)42:4<599::AID-ANR2>3.0.CO;2-F

  6. Tay SH, Mak A (2015) Anti-NR2A/B antibodies and other major molecular mechanisms in the pathogenesis of cognitive dysfunction in systemic lupus erythematosus. Int J Mol Sci 16:10281–10300. https://doi.org/10.3390/ijms160510281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Couture J, Ben-Shoshan M, Pineau CA, Scott S, Clarke AE, Bernatsky S, Vinet E (2017) Risk of allergic conditions in children born to women with systemic lupus erythematosus. Arthritis Care Res (Hoboken) 70:315–319. https://doi.org/10.1002/acr.23251

    Article  Google Scholar 

  8. Couture J, Bernatsky S, Scott S, Pineau CA, Vinet E (2018) Brief report: risk of childhood rheumatic and nonrheumatic autoimmune diseases in children born to women with systemic lupus erythematosus. Arthritis Rheumatol (Hoboken, NJ) 70:1796–1800. https://doi.org/10.1002/art.40570

    Article  Google Scholar 

  9. Tincani A, Danieli E, Nuzzo M, Scarsi M, Motta M, Cimaz R, Lojacono A, Nacinovich R, Taddei F, Doria A, Brucato A, Meroni P, Pregnancy Study Group of It (2006) Impact of in utero environment on the offspring of lupus patients. Lupus 15:801–807

    Article  CAS  PubMed  Google Scholar 

  10. Steup-Beekman G, Steens S, van Buchem M, Huizinga T (2007) Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives. Lupus 16:329–334. https://doi.org/10.1177/0961203307078224

    Article  CAS  PubMed  Google Scholar 

  11. Murashima A, Fukazawa T, Hirashima M, Takasaki Y, Oonishi M, Niijima S, Yamashiro Y, Yamataka A, Miyano T, Hashimoto H (2004) Long term prognosis of children born to lupus patients. Ann Rheum Dis 63:50–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. el-Roeiy A, Gleicher N, Isenberg D, Kennedy RC, Shoenfeld Y (1987) A common anti-DNA idiotype and other autoantibodies in sera of offspring of mothers with systemic lupus erythematosus. Clin Exp Immunol 68:528–534

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lewis SW, Owen MJ, Murray RM (1989) Obstetric complications and schizophrenia: methodology and mechanisms. In: Schulz SCTC (ed) Schizophrenia: a scientific focus. Oxford University Press, Oxford, pp 56–59

    Google Scholar 

  14. Murphy TK, Sajid M, Soto O, Shapira N, Edge P, Yang M, Lewis MH, Goodman WK (2004) Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics. Biol Psychiatry 55:61–68. https://doi.org/10.1016/S0006-3223(03)00704-2

    Article  PubMed  Google Scholar 

  15. Gariup M, Gonzalez A, Lázaro L, Torres F, Serra-Pagès C, Morer A (2015) IL-8 and the innate immunity as biomarkers in acute child and adolescent psychopathology. Psychoneuroendocrinology 62:233–242. https://doi.org/10.1016/j.psyneuen.2015.08.017

    Article  CAS  PubMed  Google Scholar 

  16. Bauer M, Goetz T, Glenn T, Whybrow PC (2008) The thyroid-brain interaction in thyroid disorders and mood disorders. J Neuroendocrinol 20:1101–1114. https://doi.org/10.1111/j.1365-2826.2008.01774.x

    Article  CAS  PubMed  Google Scholar 

  17. Morer A, Viñas O, Lázaro L, Calvo R, Andrés S, Bosch J, Gastó C, Massana J, Castro J (2006) Subtyping obsessive-compulsive disorder: clinical and immunological findings in child and adult onset. J Psychiatr Res 40:207–213. https://doi.org/10.1016/j.jpsychires.2005.04.003

    Article  CAS  PubMed  Google Scholar 

  18. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997) Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988. https://doi.org/10.1097/00004583-199707000-00021

    Article  CAS  PubMed  Google Scholar 

  19. Figueras Masip A, Amador-Campos JA, Gómez-Benito J, del Barrio Gándara V (2010) Psychometric properties of the Children’s Depression Inventory in community and clinical sample. Span J Psychol 13:990–999

    Article  PubMed  Google Scholar 

  20. Smucker MR, Craighead WE, Craighead LW, Green BJ (1986) Normative and reliability data for the Children’s Depression Inventory. J Abnorm Child Psychol 14:25–39

    Article  CAS  PubMed  Google Scholar 

  21. Birmaher B, Khetarpal S, Brent D et al (1997) The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics. J Am Acad Child Adolesc Psychiatry 36:545–553. https://doi.org/10.1097/00004583-199704000-00018

    Article  CAS  PubMed  Google Scholar 

  22. Williamson DE, Birmaher B, Ryan ND, Shiffrin TP, Lusky JA, Protopapa J, Dahl RE, Brent DA (2003) The stressful life events schedule for children and adolescents: development and validation. Psychiatry Res 119:225–241

    Article  PubMed  Google Scholar 

  23. Wechsler D (2006) Escala de Inteligencia de Wechsler para Niños, 4a edición. TEA Edicio, Madrid

    Google Scholar 

  24. Rey A (1980) Test de la Figura Compleja de Rey. TEA Edicio, Madrid

    Google Scholar 

  25. Reynolds C, Bigler E (2001) TOMAL: Test de Memoria y Aprendizaje. TEA Edicio, Madrid

    Google Scholar 

  26. Culberston WC, Zillmer EA (2006) Tower of London. Multi-Health Systems Inc, Drexel University (TOLDX), Toronto

    Google Scholar 

  27. Conners CK, Staff MHS, Connelly V et al (2000) Conners’ continuous performance test II (CPT II V. 5). Multi-Health Syst Inc 29:175–196. https://doi.org/10.1207/s15326942dn2901_9

    Article  Google Scholar 

  28. Cuetos F, Rodríguez B, Ruano E (1996) PROLEC: Batería de evaluación de los procesos lectores de los niños de educación primaria [Evaluation of reading processes of primary education students]. TEA Ediciones, Madrid, Spain

  29. Romero-Diaz J, Isenberg D, Ramsey-Goldman R (2011) Measures of adult systemic lupus erythematosus: updated version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Arthritis Care Res (Hoboken) 63(Suppl 1):S37–S46. https://doi.org/10.1002/acr.20572

    Article  Google Scholar 

  30. Snaith RP (2003) The hospital anxiety and depression scale. Health Qual Life Outcomes 1:29. https://doi.org/10.1186/1477-7525-1-29

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ezpeleta L, Guillamón N, Granero R, de la Osa N, María Domènech J, Moya I (2007) Prevalence of mental disorders in children and adolescents from a Spanish slum. Soc Sci Med 64:842–849. https://doi.org/10.1016/j.socscimed.2006.10.031

    Article  PubMed  Google Scholar 

  32. van der Linden MW, Westendorp RG, Zidane M et al (2001) Autoantibodies within families of patients with systemic lupus erythematosus are not directed against the same nuclear antigens. J Rheumatol 28:284–287

    PubMed  Google Scholar 

  33. Dean GS, Tyrrell-Price J, Crawley E, Isenberg DA (2000) Cytokines and systemic lupus erythematosus. Ann Rheum Dis 59:243–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoshio T, Okamoto H, Kurasawa K, Dei Y, Hirohata S, Minota S (2016) IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus. Lupus. 25:997–1003. https://doi.org/10.1177/0961203316629556

    Article  CAS  PubMed  Google Scholar 

  35. Sharif MN, Tassiulas I, Hu Y, Mecklenbrauker I, Tarakhovsky A, Ivashkiv LB (2004) IFN-alpha priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis. J Immunol 172:6476–6481

    Article  CAS  PubMed  Google Scholar 

  36. Llorente L, Richaud-Patin Y, García-Padilla C, Claret E, Jakez-Ocampo J, Cardiel MH, Alcocer-Varela J, Grangeot-Keros L, Alarcón-Segovia D, Wijdenes J, Galanaud P, Emilie D (2000) Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum 43:1790–1800. https://doi.org/10.1002/1529-0131(200008)43:8<1790::AID-ANR15>3.0.CO;2-2

    Article  CAS  PubMed  Google Scholar 

  37. Miller AH, Haroon E, Raison CL, Felger JC (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297–306. https://doi.org/10.1002/da.22084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stuart MJ, Singhal G, Baune BT (2015) Systematic review of the neurobiological relevance of chemokines to psychiatric disorders. Front Cell Neurosci 9:357. https://doi.org/10.3389/fncel.2015.00357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mitchell RHB, Goldstein BI (2014) Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry 53:274–296. https://doi.org/10.1016/j.jaac.2013.11.013

    Article  PubMed  Google Scholar 

  40. Ratnayake U, Quinn T, Walker DW, Dickinson H (2013) Cytokines and the neurodevelopmental basis of mental illness. Front Neurosci 7:180. https://doi.org/10.3389/fnins.2013.00180

    Article  PubMed  PubMed Central  Google Scholar 

  41. Skerry TM, Genever PG (2001) Glutamate signalling in non-neuronal tissues. Trends Pharmacol Sci 22:174–181

    Article  CAS  PubMed  Google Scholar 

  42. Gono T, Kawaguchi Y, Kaneko H, Nishimura K, Hanaoka M, Kataoka S, Okamoto Y, Katsumata Y, Yamanaka H (2011) Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 50:1578–1585. https://doi.org/10.1093/rheumatology/keq408

    Article  CAS  Google Scholar 

  43. Faust TW, Chang EH, Kowal C, Berlin R, Gazaryan IG, Bertini E, Zhang J, Sanchez-Guerrero J, Fragoso-Loyo HE, Volpe BT, Diamond B, Huerta PT (2010) Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci U S A 107:18569–18574. https://doi.org/10.1073/pnas.1006980107

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gerosa M, Poletti B, Pregnolato F, Castellino G, Lafronza A, Silani V, Riboldi P, Meroni PL, Merrill JT (2016) Antiglutamate receptor antibodies and cognitive impairment in primary antiphospholipid syndrome and systemic lupus erythematosus. Front Immunol 7:5. https://doi.org/10.3389/fimmu.2016.00005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brunner HI, Klein-Gitelman MS, Zelko F, Beebe DW, Foell D, Lee J, Zaal A, Jones J, Roebuck-Spencer T, Ying J (2014) Blood-based candidate biomarkers of the presence of neuropsychiatric systemic lupus erythematosus in children. Lupus Sci Med 1:e000038. https://doi.org/10.1136/lupus-2014-000038

    Article  PubMed  PubMed Central  Google Scholar 

  46. Natsuaki MN, Shaw DS, Neiderhiser JM, Ganiban JM, Harold GT, Reiss D, Leve LD (2014) Raised by depressed parents: is it an environmental risk? Clin Child Fam Psychol Rev 17:357–367. https://doi.org/10.1007/s10567-014-0169-z

    Article  PubMed  PubMed Central  Google Scholar 

  47. Sohr-Preston SL, Scaramella LV (2006) Implications of timing of maternal depressive symptoms for early cognitive and language development. Clin Child Fam Psychol Rev 9:65–83. https://doi.org/10.1007/s10567-006-0004-2

    Article  PubMed  Google Scholar 

  48. Conners-Burrow NA, Bokony P, Whiteside-Mansell L, Jarrett D, Kraleti S, McKelvey L, Kyzer A (2014) Low-level depressive symptoms reduce maternal support for child cognitive development. J Pediatr Health Care 28:404–412. https://doi.org/10.1016/j.pedhc.2013.12.005

    Article  PubMed  Google Scholar 

  49. Evans J, Melotti R, Heron J, Ramchandani P, Wiles N, Murray L, Stein A (2012) The timing of maternal depressive symptoms and child cognitive development: a longitudinal study. J Child Psychol Psychiatry 53:632–640. https://doi.org/10.1111/j.1469-7610.2011.02513.x

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Antonio Angulo, neuropsychologist, who took the neuropsychological tests; Dr. Odette Vinyas, immunologist, who contributed in running the immunological tests; and Dr. Roger Borrás for the help in the preliminary statistical analysis.

Funding

This work was partially financed by FIS (Fund for Investigation in Health) grant no. PI040700 from the Health Ministry of Spain. MG was partly supported by an “After-Specialization-Grant” (Beca de Fin de Residencia) by the Hospital Clinic Foundation.

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Authors and Affiliations

  1. Faculty of Medicine and Health Sciences, University of Barcelona, c/ Villarroel 170, 08036, Barcelona, Spain

    Maria Gariup, Carles Serra-Pagès, Luisa Lázaro, Ricard Cervera & Astrid Morer

  2. Psykiatrien i Region Hovedstaten, Afd. C270Ø, Nordre Fasanvej 57, 2300, Frederiksberg, Denmark

    Maria Gariup

  3. Department of Child and Adolescent Psychiatry and Psychology, Hospital Clínic de Barcelona, c/ Villarroel 170, 08036, Barcelona, Spain

    Sara Lera-Miguel, Eva Varela, Luisa Lázaro & Astrid Morer

  4. Biostatistics and Data Management Core Facility, IDIBAPS, c/ Villarroel 170, 08036, Barcelona, Spain

    Ferrán Torres

  5. Biostatistics Unit, School of Medicine, Universitat Autònoma de Barcelona, Plaça Cívica, Campus de la UAB, 08193 Cerdanyola del Vallès, Barcelona, Spain

    Ferrán Torres

  6. August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

    Carles Serra-Pagès, Azucena González-Navarro, Gerard Espinosa, Luisa Lázaro & Astrid Morer

  7. Immunology Department, Hospital Clínic de Barcelona, c/ Villarroel 170, 08036, Barcelona, Spain

    Carles Serra-Pagès & Azucena González-Navarro

  8. Department of Autoimmune Diseases, Hospital Clínic de Barcelona, c/ Villarroel 170, 08036, Barcelona, Spain

    Gerard Espinosa & Ricard Cervera

  9. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029, Madrid, Spain

    Luisa Lázaro & Astrid Morer

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  1. Maria Gariup
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Gariup, M., Lera-Miguel, S., Torres, F. et al. Autoantibodies, elevated cytokines, and neurocognitive abnormalities in offspring of women with systemic lupus erythematosus: comparison with healthy controls. Clin Rheumatol 38, 2529–2539 (2019). https://doi.org/10.1007/s10067-019-04495-4

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